Zhu An, Yan Xueqing, Chen Mengting, Lin Yifan, Li Lanqian, Wang Yufei, Huang Jiabin, He Jiale, Yang Mengchen, Hua Wenxi, Chen Kunqi, Qi Jing, Zhou Zixiong
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, 1 Xue Fu North Road, Fuzhou 350122, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, No.1, Xuefu North Road, University Town, Fuzhou, Fujian 350122, China.
Phytomedicine. 2025 Jan;136:156341. doi: 10.1016/j.phymed.2024.156341. Epub 2024 Dec 20.
Metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory lipotoxic disorder marked by hepatic steatosis, hepatocyte damage, inflammation, and varying stages of fibrosis. Sappanone A (SA), a flavonoid, exhibits anti-inflammatory and hepatoprotection activities. Nevertheless, the effects of SA on MASH remain ambiguous. We evaluated the effects of SA on hepatocyte lipotoxicity, inflammation, and fibrosis conditions in MASH mice, as well as the underlying mechanisms.
A conventional murine MASH model fed a methionine-choline-deficient (MCD) diet was utilized to assess the role of SA on MASH in vivo. Drug target prediction and liver transcriptomics were employed to elucidate the potential actions of SA. AML12 cells were applied to further explore the effects and mechanisms of SA in vitro.
The in silico prediction indicated that SA could modulate inflammation, insulin resistance, lipid metabolism, and collagen catabolic process. Treating with SA dose-dependently lessened the elevated levels of serum ALT and AST in mice with diet-triggered MASH, and high-dose SA treatment exhibited a similar effect to silymarin. Additionally, SA treatment significantly reduced lipid deposition, inflammation, and fibrosis subjected to metabolic stress in a dose-dependent manner. Besides, SA mitigated palmitate-triggered lipotoxicity in hepatocytes. Liver transcriptomics further confirmed the aforementioned findings. Of note, mRNA-sequencing analysis and molecular biology experiments demonstrated that SA statistically up-regulated the hepatic expression of major urinary protein 3 (Mup3), thereby facilitating lipid transportation and inhibiting lipotoxicity. Furthermore, Mup3 knockdown in hepatocytes significantly abolished the hepatoprotection provided by SA.
SA alleviates MASH by decreasing lipid accumulation and lipotoxicity in hepatocytes, at least partially by targeting Mup3, and subsequently blocks MASH process. Therefore, SA could be a promising hepatoprotective agent in the context of MASH.
代谢功能障碍相关脂肪性肝炎（MASH）是一种炎症性脂毒性疾病，其特征为肝脂肪变性、肝细胞损伤、炎症以及不同阶段的纤维化。苏木酮A（SA）是一种黄酮类化合物，具有抗炎和肝脏保护活性。然而，SA对MASH的影响仍不明确。我们评估了SA对MASH小鼠肝细胞脂毒性、炎症和纤维化状况的影响及其潜在机制。
采用喂食蛋氨酸-胆碱缺乏（MCD）饮食的传统小鼠MASH模型来评估SA在体内对MASH的作用。利用药物靶点预测和肝脏转录组学来阐明SA的潜在作用。应用AML12细胞在体外进一步探究SA的作用及其机制。
计算机模拟预测表明，SA可调节炎症、胰岛素抵抗、脂质代谢和胶原蛋白分解代谢过程。用SA治疗可剂量依赖性地降低饮食诱发的MASH小鼠血清谷丙转氨酶（ALT）和谷草转氨酶（AST）升高的水平，高剂量SA治疗表现出与水飞蓟宾相似的效果。此外，SA治疗以剂量依赖性方式显著减少了代谢应激引起的脂质沉积、炎症和纤维化。此外，SA减轻了棕榈酸酯引发的肝细胞脂毒性。肝脏转录组学进一步证实了上述发现。值得注意的是，mRNA测序分析和分子生物学实验表明，SA在统计学上上调了主要尿蛋白3（Mup3）的肝脏表达，从而促进脂质转运并抑制脂毒性。此外，肝细胞中Mup3的敲低显著消除了SA提供的肝脏保护作用。
SA通过减少肝细胞中的脂质积累和脂毒性来减轻MASH，至少部分是通过靶向Mup3，随后阻断MASH进程。因此，在MASH背景下，SA可能是一种有前景的肝脏保护剂。
